Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.

Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective GLS inhibitor, when combined with azacytidine (AZA), in vitro and in vivo, followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with telaglenastat/AZA led to an ORR of 70% with CR/mCRs in 53% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells; was associated with clinical responses to telaglenastat/AZA and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.

Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms.

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

Development of TP53 mutations over the course of therapy for acute myeloid leukemia.

TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy. Twenty-nine patients (15%) developed a newly detectable TP53 mutation in the context of relapsed/refractory disease. The median variant allelic frequency (VAF) was 15% (range, 1.1%-95.6%). TP53 mutations were more common after intensive therapy versus lower-intensity therapy (23% vs. 10%, respectively; p = 0.02) and in patients who had undergone hematopoietic stem cell transplant versus those who had not (36% vs. 12%, respectively; p = 0.005). Lower TP53 VAF was associated with an increased likelihood of complete remission (CR) or CR with incomplete hematologic recovery (CRi) compared to higher TP53 VAF (CR/CRi rate of 41% for VAF < 20% vs. 13% for VAF ≥ 20%, respectively). The median overall survival (OS) after acquisition of TP53 mutation was 4.6 months, with a 1-year OS rate of 19%. TP53 VAF at relapse was significantly associated with OS; the median OS of patients with TP53 VAF ≥ 20% was 3.5 months versus 6.1 months for those with TP53 VAF < 20% (p < 0.05). In summary, new TP53 mutations may be acquired throughout the course of AML therapy. Sequential monitoring for TP53 mutations is likely to be increasingly relevant in the era of emerging TP53-targeting therapies for AML.

A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome.

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.

Novel monoclonal antibody-based treatment strategies in adults with acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) has a poor overall survival compared with pediatric ALL where cure rates are observed in more than 90% of patients. The recent development of novel monoclonal antibodies targeting CD20, CD19, and CD22 has changed the long-term outcome of this disease, both in the frontline setting (e.g. rituximab) and for patients with relapsed/refractory disease (e.g. inotuzumab ozogamicin and blinatumomab). The CD3-CD19 bispecific T-cell-engaging antibody blinatumomab is also the first drug approved in ALL for patients with persistent or recurrent measurable residual disease, providing a new treatment paradigm for these patients. Several new agents are also in development that use novel constructs or target alternative surface epitopes such as CD123, CD25, and CD38. Herein, we review the role of monoclonal antibodies in adult ALL and summarize the current and future approaches in ALL, including novel combination therapies and the possibility of early incorporation of these agents into treatment regimens.

Venetoclax-based therapies for acute myeloid leukemia.

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.

Falla hepática aguda sobre crónica / Acute-On-Chronic Liver Failure

La falla hepática aguda sobre crónica (ACLF, del inglés Acuteon Chronic Liver Failure) comprende el deterioro agudo de la función hepática en un paciente que tiene de base una enfermedad hepática crónica de novo o conocida y desencadenada por diferentes factores precipitantes que pueden ser hepáticos o extrahepáticos. Dentro de las manifestaciones clínicas se encuentran: disfunción renal, encefalopatía hepática y falla orgánica multisistémica, que de no ser tratadas oportunamente se traducen en mal pronóstico. Se han utilizado varias puntuaciones para valorar la función hepática y el pronóstico de los pacientes. A pesar de que la falla orgánica multisistémica es una contraindicación para el trasplante hepático, este sigue siendo la mejor opción de tratamiento para estos pacientes

Acute-on-chronic liver failure (ACLF) includes acute deterioration of liver functions in patients with either chronic de novo liver disease or already diagnosed liver disease. ACLF can be triggered by various hepatic or extrahepatic precipitating factors. Among its clinical manifestations are renal dysfunction, hepatic encephalopathy, and multisystem organ failure. If not treated promptly translate the prognosis can be poor. Several scoring systems have been used to assess liver function and patient prognosis. Although multisystem organ failure contraindicates liver transplantation, it remains the treatment of choice for this patients

Enfermedad renal crónica en pacientes trasplantados de hígado en el Hospital Pablo Tobón Uribe 2005-2013 / Chronic Kidney Disease in Liver Transplant Patients in the Hospital Pablo Tobón Uribe 2005-2013

Avances en la terapia inmunosupresora han revolucionado los resultados a largo plazo del trasplante de hígado, sin embargo esto ha incrementado la prevalencia de enfermedad renal crónica (ERC); existen algunos factores de riesgo asociados como el uso de inhibidores de calcineurínicos, la presencia de diabetes e hipertensión. El objetivo de este estudio es determinar la incidencia de ERC en los pacientes trasplantados de hígado del hospital Pablo Tobón Uribe durante los años 2005-2013 y evaluar las complicaciones asociadas. Metodología: cohorte retrospectiva. Resultados: se evaluaron 215 pacientes trasplantados de hígado, la edad mediana fue de 50,37 años (DE ± 12,6), el 42,8% mujeres; 3,3% de los pacientes necesitaron terapia de reemplazo renal al primer mes del trasplante; la terapia inmunosupresora más utilizada fue ciclosporina en el 90,7%. Durante el seguimiento la tasa de filtración disminuye con el tiempo, con una mediana de 86,2 mL/min/1,73 (DE ± 25,9) al momento del trasplante y llegando a 74,2 mL/min/1,73 (DE ± 24,5) a 3 años de seguimiento. La velocidad de deterioro de la función renal por medio del modelo de ecuaciones generalizadas estimadas fue de 3,5 mL/año (IC: 95% 2,44-4,74, p= 0,000). Al momento del trasplante de hígado el 16,3% de los pacientes presentaban una TFG menor a 60 mL/min; a tres años de seguimiento fue de 29,6%; al agrupar las complicaciones encontradas, según presencia o no de disfunción renal al final del seguimiento, encontramos que a excepción de la muerte, la presencia de enfermedad cerebrovascular y enfermedad coronaria fue similar en ambos grupos. Conclusión: la ERC es una complicación frecuente en los pacientes trasplantados de hígado, nuestra recomendación es el control frecuente de los marcadores de daño renal.

Advances in immunosuppressive therapy have revolutionized long-term results of liver transplantation, but this has increased the prevalence of chronic kidney disease (CKD). Some risk factors including diabetes and hypertension are associated with the use of calcineurin inhibitors. The objective of this study is to determine the incidence of CKD in liver transplant patients at the Hospital Pablo Tobon Uribe from 2005 to 2013 and then assess associated complications. Methods: This is a retrospective cohort study. Results: This study evaluated 215 patients with liver transplants. Average patient age at transplant was 50.37 years (SD +/- 12.6), and 42.8% of the patients were women. Kidney replacements were required by 3.3% of the patients within the first month after liver transplantation. The most frequently used immunosuppressive therapy was cyclosporine which was used for 90.7% of the patients. During follow-up, the filtration rate decreased over time with a median of 86.2ml/min/1.73 (SD +/- 25.9) at transplant. This reached 74.2ml/min/1.73 (SD +/- 24.5) at 3 years follow-up. The rate of deterioration of renal function determined by generalized estimated equations was 3.5ml/year (95% CI 2.44 to 4.74, p = 0.000). At the time of liver transplantation 16.3% of patients had glomerular filtration rates of less than 60ml/min. After three years of follow-up, 29.6% of patients had glomerular filtration rates of less than 60ml/min. By grouping complications such as the presence or absence of renal dysfunction at follow-up, we found that, except for death, the presence of cerebrovascular disease and coronary heart disease was similar in both groups. Conclusion: CKD is a frequent complication in liver transplant patients. Our recommendation is frequent monitoring of kidney damage markers.

[Amitraz poisoning]. / Intoxicación por amitraz.

Poisoning due to amitraz together with its solvent xilene, is an unusual condition although may be increasing in rural areas where it is used as insecticide-ectoparasiticide.1-3 At present, there is scare references to orient physicians concerning its handling in childhood. We present the case of a 2-year-old boy who suffered an accidental intake of amitraz and was admitted into our Pediatric Intensive Care Unit requiring mechanical ventilation. We consider the usefulness of informing the medical community about this case so as to be aware of this rare kind of poisoning in our community.

Intoxicación por amitraz / Amitraz poisoning

En nuestro medio, la intoxicación por amitraz y su solvente xileno es una patología poco frecuente, pero puede observarse un aumento en zonas rurales, donde se lo emplea como insecticida-ectoparasiticida. Por tal razón, se cuenta con escasa bibliografía que oriente su manejo en niños. Presentamos el caso de un paciente de 2 años de edad, con ingestión accidental de amitraz, internado en nuestra Unidad de Cuidados Intensivos Pediátricos y que requirió ventilación mecánica. Creemos que comunicar este caso puede ser útil para alertar sobre esta intoxicación, poco frecuente en nuestro medio.

Poisoning due to amitraz together with its solvent xilene, is an unusual condition although may be increasing in rural areas where it is used as insecticide-ectoparasiticide. At present, there is scare references to orient physicians concerning its handlingin childhood. We present the case of a 2-year-old boy who suffered an accidental intake of amitraz and was admitted into our Pediatric Intensive Care Unit requiring mechanical ventilation. We consider the usefulness of informing the medical community about this case so as to be aware of this rare kind of poisoning in our community.

Intoxicación por amitraz / Amitraz poisoning

En nuestro medio, la intoxicación por amitraz y su solvente xileno es una patología poco frecuente, pero puede observarse un aumento en zonas rurales, donde se lo emplea como insecticida-ectoparasiticida. Por tal razón, se cuenta con escasa bibliografía que oriente su manejo en niños. Presentamos el caso de un paciente de 2 años de edad, con ingestión accidental de amitraz, internado en nuestra Unidad de Cuidados Intensivos Pediátricos y que requirió ventilación mecánica. Creemos que comunicar este caso puede ser útil para alertar sobre esta intoxicación, poco frecuente en nuestro medio.(AU)

Poisoning due to amitraz together with its solvent xilene, is an unusual condition although may be increasing in rural areas where it is used as insecticide-ectoparasiticide. At present, there is scare references to orient physicians concerning its handlingin childhood. We present the case of a 2-year-old boy who suffered an accidental intake of amitraz and was admitted into our Pediatric Intensive Care Unit requiring mechanical ventilation. We consider the usefulness of informing the medical community about this case so as to be aware of this rare kind of poisoning in our community.(AU)